Interaction of CR6 (GADD45γ) with Proliferating Cell Nuclear Antigen Impedes Negative Growth Control

Azam, Naiyer; Vairapandi, Mariappan; Zhang, Wei; Hoffman, Barbara; Liebermann, Dan A.

doi:10.1074/jbc.m005626200

Cited by 86 publications

(83 citation statements)

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“…Colony re-plating assays, which reflect proliferative capability of progenitor cells (Nakahata and Ogawa, 1982), have indicated prolonged proliferation capacity of gadd45a-deficient and gadd45b-deficient BM-derived CFU-GM progenitors. This may be indicative of the negative growth regulatory function of gadd45 proteins and their ability to interact with p21 (Vairapandi et al, 1996;Azam et al, 2001) to modulate this function.…”

Section: Discussionmentioning

confidence: 99%

“…These observations raise the possibility that deficiency in either gadd45b or gadd45a alters the function of the hematopoietic stem cell compartment in response to physiological stress. In this regard, it will be of interest to assess the possible role of Gadd45 protein interaction with p21 (Vairapandi et al, 1996;Azam et al, 2001), which has been implicated in the regulation of hematopoietic stem cell quiescence and cell survival (Asada et al, 1999;Cheng et al, 2000;Marone et al, 2002). Inflammatory signals arising from IP administration of sodium caseinate, which is known to rapidly stimulate myelopoiesis in murine BM (Liebermann and HoffmanLiebermann, 1989), failed to stimulate myelopoiesis in gadd45aÀ/À and gadd45bÀ/À mice, impairing accumulation of myeloid cells in the peritoneum.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, Gadd45a, Gadd45b and Gadd45g have been implicated in cell cycle arrest (Beadling et al, 1993;Hollander et al, 1999;Wang et al, 1999;Zhang et al, 1999), DNA repair (Smith et al, 1994;Vairapandi et al, 1996), apoptosis (Harkin et al, 1999;Vairapandi et al, 2000;Azam et al, 2001;Takekawa et al, 2002;Yoo et al, 2003), cell survival (Smith et al, 1996;De Smaele et al, 2001;Zazzeroni et al, 2003;Papa et al, 2004;Gupta et al, 2005), genomic stability (Hollander et al, 1999), inflammatory response and innate immunity (Lu et al, 2001;Yang et al, 2001;Lu et al 2004). Gadd45 proteins have been shown to stimulate the p38-c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways in response to stress situations and thereby sensitize cells for growth arrest, apoptosis or survival (Takekawa and Saito, 1998;Harkin et al, 1999;De Smaele et al, 2001;Lu et al, 2001;Hildesheim et al, 2002;Yoo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Gupta

Hoffman

et al. 2006

Oncogene

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Gupta

Hoffman

et al. 2006

Oncogene

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“…PCNA-Work conducted in our laboratory and in the laboratory of Dr. Albert Fornace (Georgetown University) has shown that all three Gadd45 proteins interact with PCNA (11,23,33), a nuclear protein that plays a central role in DNA repair and replication (38-39 & therein). It was suggested that interaction of Gadd45a with PCNA is involved in nucleotide excision repair (NER) of DNA (24).…”

Section: Gadd45 Mode Of Action: Interaction With Partner Proteinsmentioning

confidence: 99%

“…Recently, we have shown that both Gadd45b and Gadd45g also interact with the cdc2/cyclinB1 complex and inhibit cdc2 kinase activity following exposure of cell to genotoxic stress (2). p21-We have shown that all three Gadd45 proteins interact with the cyclin dependent kinase inhibitor p21 (11,33), a p53 target gene (45) implicated in G1/S (46-49) and G2/M (50) cell cycle arrest. The role of Gadd45 protein interactions with p21 is still unclear.…”

Section: Unpublished and 11)mentioning

confidence: 99%

Gadd45 in the response of hematopoietic cells to genotoxic stress

Liebermann

Hoffman

2007

Blood Cells, Molecules, and Diseases

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Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in either cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Recently we have taken advantage of gadd45a and gadd45b deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. Myeloid enriched BM cells from gadd45a and gadd45b deficient mice were observed to be more sensitive to ultraviolet radiation (UVC), VP-16 and daunorubicin (DNR) induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a and gadd45b deficient cells was evident also by enhanced activation of caspase-3 and PARP cleavage and decreased expression of cIAP-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45 deficient BM cells restored the wt apoptotic phenotype. Both gadd45a and gadd45b deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Additional work conducted in this laboratory has shown that in hematopoietic cells exposed to UV radiation gaddd45a and gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the Gadd45a-p38-NF-kB mediated survival pathway and Gadd45b mediated inhibition of the stress response MKK4-JNK pathway (59). These data reveal novel mechanisms that mediate the pro-survival functions of gadd45a and gadd45b in hematopoietic cells following UV irradiation. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs. This knowledge should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukaemias and response of normal and malignant hematopoietic cells to chemo and radiation therapy. These observations set the stage to evaluate, in clinically relevant settings, the impact that the status of gadd45a and gadd45b might have on the efficacy of DNR or VP-16 in killing leukemic cells.

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Apoptosis of glomerular mesangial cells induced by sublytic C5b‐9 complexes in rats with Thy‐1 nephritis is dependent on Gadd45γ upregulation

et al. 2009

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The complement C5b-9 complexes can result in cell apoptosis, but the mechanism of sublytic C5b-9-mediated glomerular mesangial cell (GMC) apoptosis in Thy-1 nephritis (Thy-1N) remains largely unclear. The Gadd45 gene is involved in the cellular response to DNA damage and can promote cell apoptosis. In this study, both Gadd45c expression patterns and pathologic changes of renal tissue were examined in rat Thy-1N. Both Gadd45c expression and GMC apoptosis were significantly decreased in Thy-1N rats upon the depletion of complement with cobra venom factor. Our in vitro studies showed that Gadd45c over-expression increased sublytic C5b-9-induced GMC apoptosis, while Gadd45c gene knockdown by siRNA greatly reduced GMC apoptosis. Moreover, Gadd45c gene silencing in vivo markedly inhibited the pathologic changes in the renal tissue of Thy-1N rats. These data suggest that Gadd45c gene expression is involved in regulating GMC apoptosis mediated by sublytic C5b-9 in Thy-1N.Key words: Apoptosis . Gadd45c . Glomerular mesangial cells . Sublytic C5b-9 .Thy-1 nephritis Supporting Information available online IntroductionMesangioproliferative glomerulonephritis (MsPGN) is a disease with high incidence in humans. Proliferation of glomerular mesangial cells (GMC) in MsPGN appears to be crucial for a subsequent increase in mesangial matrix and development of glomerulosclerosis [1,2]. Rat Thy-1 nephritis (Thy-1N), namely anti-thymocyte serum (ATS) induced nephritis, is a widely used animal model for studying human MsPGN [3,4]. ATS administered in rats binds to Thy-1 antigen on the membrane of GMC and then activates the complement system resulting in immunopathologic injury [5][6][7][8]. Complement activation results in generation of chemotactic factors, such as C5a, and formation of the C5b-9 complex [6,9]. Because GMC damage in Thy-1N is complement-dependent and neutrophil-independent, complement is generally regarded as the principal mediator of GMC lesions in the rats with Thy-1N. Assembly of C5b-9 can result in formation of transmembrane channels or rearrangement of membrane lipid with loss of membrane integrity. However, injury to nucleated cells by C5b-9 is almost non-lytic (sublytic) because the cell surface has many homologous restriction factors such as CD59 and MCP. Sublytic C5b-9 complexes can trigger [4,6,9,10]. Complement deposits are observed in the glomeruli of patients with MsPGN [1,2]. Our previous studies have also revealed the deposition of sublytic C5b-9 complexes on GMC surfaces in Thy-1N rats [9], but the role of sublytic C5b-9 complexes in Thy-1N has not been fully elucidated. During the progression of Thy-1N, GMC undergo two phases of change: early apoptosis/necrosis and secondary proliferation [4,9,11]. The mechanisms governing GMC apoptosis during the early stage of Thy-1N, including the genes involved in GMC apoptosis, remain unclear [12,13]. The growtharrest-and DNA-damage-inducible protein 45 (Gadd45) gene family, which encodes proteins that play important roles in controlling cell growth, has been im...

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Interaction of CR6 (GADD45γ) with Proliferating Cell Nuclear Antigen Impedes Negative Growth Control

Cited by 86 publications

References 47 publications

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation

Gadd45 in the response of hematopoietic cells to genotoxic stress

Apoptosis of glomerular mesangial cells induced by sublytic C5b‐9 complexes in rats with Thy‐1 nephritis is dependent on Gadd45γ upregulation

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